This TRD, Magnetic Resonance Spectroscopy (MRS) and Multinuclear Imaging, has been actively involved in the development and evaluation of in vivo MRS and spectroscopic imaging (MRSI) technology for both protons (1H) and other nuclei from the founding of the CAMRTS P41 Research Resource Center in 1995 to the present. While some of our recent metabolic imaging studies involved a variety of organs including kidney, heart, and liver, our primary effort during the prior funding cycle was on the development of novel methods for measuring brain neurotransmitter levels and neurometabolic processes. Under this competitive renewal, we propose to build upon our successes in brain imaging technology with important refinements needed to translate hyperpolarized 13C MRSI techniques from animal to human applications, improve 1H MRS measures of steady-state neurotransmitter levels, and provide previously unavailable regional measures of neuroenergetic and neurotransmitter cycling rates throughout the human brain. These choices are based on meeting the current and future needs of collaborative projects ?Metabolic Therapy of GBM guided by MRS of hyperpolarized 13C-pyruvate? (PI: Lawrence Recht, Stanford University), ?1H MRS of GABA, Glu, and Gln? [PI: Brian Wandell, Stanford University), and Neuroimaging of Alcoholism (PI: Adolf Pfefferbaum, SRI International). Specifically, in vivo MRSI offers non-invasive identification, visualization, and quantification of brain biochemical markers and neurotransmitters, the assessment of abnormalities in injured or diseased brain tissue, the longitudinal monitoring of degenerative diseases, and the early evaluation of therapeutic interventions. 1H MRS is able to measure steady-state levels of GABA, glutamate (Glu), and glutamine (Glu), and infusion of 13C labeled substrates permits the measurement of tricarboxylic acid (TCA) cycle and neurotransmitter cycling rates. Furthermore, the ongoing development of hyperpolarized agents, i.e., MRIvisible compounds whose magnetization is four orders of magnitude higher than that normally achieved at in vivo temperatures, presents unprecedented opportunities to noninvasively monitor critical dynamic metabolic processes under both normal and pathologic conditions. New MRS technology will be developed in accordance with the following Specific Aims: 1) to develop optimized pulse sequences and hardware for clinical hyperpolarized 13C studies of the human brain and glioma treatment response, 2) to develop improved 1H MRS GABA, Glu, and Gln editing methods to robustly measure steady-state neurotransmitter levels throughout the human brain free from overlapping macromolecular resonances that limit current methods, and 3) to develop indirect-detection 1H-13C techniques to measure TCA and Glu/Gln cycling rates throughout the human brain.